The present invention relates to a method for treating a patient using targeted hysteresis therapy. In particular, it relates to a method of treating patients using site directed hysteresis heat loss.
Diseases of the human body such as malignant tumours are generally treated by excision, chemotherapy, radiotherapy or a combination of these approaches. Each of these is subject to limitations which effects clinical utility. Excision may not be appropriate where the disease presents as a diffuse mass or is in a surgically inoperable locality. Chemotherapeutic agents are generally non-specific, thus resulting in the death of normal and diseased cells. As chemotherapy, radiotherapy is also nonspecific and results in the death of normal tissues exposed to ionising radiation. Furthermore, some diseases such as tumours may be relatively resistant to ionizing radiation. This is a particular problem with the core of a tumour mass.
Hyperthermia has been proposed as a cancer treatment. There is a great deal of published evidence to confirm that hyperthermia is effective in treating diseases like cancerous growths. The therapeutic benefit of hyperthermia therapy is mediated through two principal mechanisms: (1) a directly tumouricidal effect on tissue by raising temperatures to greater than 42xc2x0 C. resulting in irreversible damage to cancer cells; and (2) hyperthermia is known to sensitise cancer cells to the effects of radiation therapy and to certain chemotherapeutic drugs. The lack of any cumulative toxicity associated with hyperthermia therapy, in contrast to radiotherapy or chemotherapy, is further justification for seeking to develop improved systems for hyperthermia therapy.
Mammalian cells sustain hyperthermic damage in a time/temperature and cell-cycle dependant manner. This cellular response to heat is in turn modified by a variety of intra- and extra-cellular environmental factors. The intra-cellular factors that influence hyperthermic cell damage include intrinsic variation between different species, organs and even cell lines. The extra-cellular factors include the oxygen and nutritional status of cells, the pH of the extra-cellular mileiu, the absolute temperature rise and the hyperthermic duration.
Although there is some evidence that neoplastic cells are more sensitive than their normal tissue counterparts to the effects of hyperthermia, this is not a universal finding and several recent studies have demonstrated that tissue susceptibility to hyperthermic damage is not strongly linked to a cell""s neoplastic-normal status.
A number of studies have confirmed that hyperthermia and radiotherapy are synergistic. Even small fractions of a degree of temperature variation can significantly alter the prospects of cells surviving a radiation insult.
Factors affecting the synergistic action of hyperthermia and radiotherapy include the degree of duration of hyperthermia, the sequence of hyperthermia and radiotherapy, the fractionated and total dose of radiation, the pH of the extra-cellular milieu, the oxic state and nutrient status of cells and the histological type and malignant status of the cells.
Cells in the central avascular compartment of tumours are invariably acidotic hypoxic and in a state of nutritional deprivation. All these factors appear to potentiate independently the effect of hyperthermia. By the same token, severely hypoxic cells are approximately, three times more resistant to ionising radiation than oxic cells. Of major importance is the fact that although these hypoxic cells might survive the effects of radiation, hyperthermia can partly overcome this radioresistance and can potentiate radiotherapeutic killing of acidotic and hypoxic cells.
There are many problems associated with the currently available methods for inducing clinical hyperthermia in patients. Normal body tissues and organs are heat sensitive and at temperatures of greater than 42xc2x0 C. many tissues will undergo irreversible damage. The current available methods of delivering clinical hyperthermia are non-specific and will heat normal tissues as well as tumour cells. Almost all heating techniques create heat generation over a broad target area with little specificity for diseased tissue, although focussing devices for both ultrasound and electromagnetic heat generation are now being developed to improve the concentration of heat generation in more defined target areas.
Several techniques are currently available for inducing clinical hyperthermia either regionally, in selected local regions of specific organs or over the whole body. Some of these techniques are discussed below.
Whole body hyperthermia may be induced by endogenous or exogenous heat sources, but is generally not tolerated above 42xc2x0 C. without anaesthesia. Regional hyperthermic techniques include organ perfusion, various forms of electromagnetic radiation, or ultrasound.
Plain wave electromagnetic or ultrasound heating is limited by poor tissue penetration and a rapid decline of energy with increasing depth.
Ultrasound at frequencies of from 0.3 to 3 MHz is limited by the perturbations induced by tissue interfaces such as air, bone etc. However, improved focussing devices are being developed that may make this a more acceptable form of heating for deep tissues.
Microwave heating at frequencies between 434 and 2450 MHz has been used, although there is generally poor tissue penetration. Phase array devices are able to focus microwave energy in deep tissues, but variation in the heating effect remains a problem.
Radiofrequency waves at frequencies up to 434 MHz have been used with some success. These heating techniques include both dielectric and inductive modalities and can result in relatively even tissue heating. However, focussing for deep organ heating using inductive current remains a problem.
There are two basic requirements for such therapies to be effective. First, there is a need to localise the treatment to the target site. Second, there is a need to maximise heating within the diseased tissue while maintaining hyperthermia therapy within safe operating limits for the patient.
While considerable success has been observed in treating superficial tumours using hyperthermia therapy, there remains a need for a method of selectively targeting and treating diseased tissue in a patient. Major limitations due to insufficient penetration depth and poor focussing capabilities of externally applied microwave or ultrasound beams have grossly restricted a physicians ability to deliver an adequate heat load to deep seeded diseased without any unacceptable level of coincident damage to surrounding healthy tissue. The present invention seeks to ameliorate at least the problems associated with penetration depth and inadequate localisation of heat when using hyperthermia therapy.
The present invention provides an improved method for site specific treatment of diseased tissue in a patient, which comprises the steps of:
(i) selecting at least a magnetic material which has a magnetic heating efficiency of at least about 4.5xc3x9710xe2x88x928 J.m./A.g, when magnetic field conditions are equal to or less than about 7.5xc3x97107 A/s;
(ii) delivering the magnetic material to diseased tissue in a patient; and
(iii) exposing the magnetic material in the patient to a linear alternating magnetic field with a frequency of greater than about 10 kHz and a field strength such that the product of field strength, frequency and the radius of the exposed region is less than about 7.5xc3x97107 A/s to generate hysteresis heat in the diseased tissue.
Preferably, steps (i) to (iii) in the method are repeated until the diseased tissue has been destroyed or treated sufficiently to ameliorate the disease.
The magnetic material employed in the method of the invention must have a magnetic heating efficiency (MHE) of greater than about 4.5xc3x9710xe2x88x928 J.m./A.g, when magnetic field conditions are equal to or less than about 7.5xc3x97107 A/s. Preferably, a magnetic material is selected which has a MHE of greater than about 7xc3x9710xe2x88x928 J.m./A.g, when magnetic field conditions are equal to or less than 7.5xc3x97107 A/s. Most preferably, a magnetic material is selected which has a MHE of greater than about 1xc3x97107 J.m./A.g, when magnetic field conditions are equal to or less than about 7.5xc3x97107 A/s.
Advantages gained by using a magnetic material with a large MHE include:
1) improved therapeutic effectiveness by virtue of the fact that higher tumour temperatures can be reached more quickly (the effectiveness of hyperthermia therapy improves markedly as temperature is increased beyond 42xc2x0 C.);
2) reduced toxic side effects because:
i. less microcapsules need to be used to achieve therapeutic heating in tumours (advantageous if the microcapsules have any intrinsic toxicity),
ii. a lower magnetic field strength, H, can be used,
iii. more rapid heating of the tumour may be achieved which implicates less of the healthy tumour tissue immediately surrounding the tumour. (the longer time required to heat the tumour the more the immediately surrounding tissue will be heated by thermal conduction);
3) increased likelihood of successful treatment especially for tumours that would otherwise be expected to only receive a marginal benefit;
4) the techniques have a wider applicability for the treatment of different types of cancer;
5) using reduced field strengths eases engineering difficulties associated with machine design;
6) using reduced field strengths means reduced electrical power consumption and cooling requirements while running the machine.
The selection of magnetic material suitable for use in the present invention is based on the MHE of the material. MHE may be calculated using the following formula:                                                         MHE              =                                                P                  hyst                                                  f                  ·                  H                                                                                        (J·m/A·g)                                                          (        1        )            
where Physt is the heating power generated by magnetic hysteresis loss effects (units W/g), H is the amplitude of the applied magnetic field (units A/m) and f is the frequency of the applied magnetic field. The major limitations to the generation of heat by magnetic hysteresis for the purposes of treating diseased tissue, arise from the effect a time varying magnetic field has on living tissue. In general these effects increase as the product of f and H increases. Hence, it is essential that Physt be maximised subject to minimising the product of f and H.
Further, Physt can be calculated using the following formula:
Physt=f.W(W/g)xe2x80x83xe2x80x83(2)
where W is the hysteresis heat energy (units J/g) generated in the magnetic material during each cycle of the applied magnetic field and f is the frequency as before.
Combining equations (1) and (2) and eliminating f it can be seen that MHE can be calculated once H and W are known. W must be measured experimentally for each value of H. This may be achieved in the manner described herein. The MHE is then calculated from equations (1) and (2).
W can be determined using several different methods described below:
1) For magnetic hysteresis measurements a Vibrating Sample to Magnetometer (VSM) is used to measure W. A known quantity (typically less than 1 g) of the magnetic powder is fixed in a non-magnetic, non-metallic VSM sample container using a non-magnetic epoxy. Samples are in an initially demagnetised state and the value of W is determined at successively higher field strengths.
2) A 50 Hz Alternating Field Magnetometer is also be used to measure W. Samples prepared as for the VSM are placed inside a small coil. This small coil is then placed between the pole pieces of a magnet that produces a magnetic field alternating at 50 Hz. The voltage induced in this coil is equal to N.dB/dt where N is the number of turns in the coil. This voltage signal is integrated, corrected for air flux and a plot of magnetisation, M, vs H is generated. This is the hysteresis loop the area of which equals W.
3) An alternative to these methods is to take a known quantity of the magnetic powder, typically 125 mg, and disperse it in 5 ml of agar gel (3% agar dissolved in warm water. The agar solidifies when cooled back to room temperature. ) A temperature probe is inserted into the gel and the whole exposed to the alternating magnetic field of desired strength. From the resultant curve of Temperature vs Time it is possible to calculate W at H.
Any magnetic material which exhibits hysteresis and which has a MHE of greater than 4.5xc3x9710xe2x88x928 J.m./A.g, when magnetic field conditions are equal to or less than about 7.5xc3x97107 A/s may be used in the present invention. Preferably, the magnetic materials are ferromagnetic materials. Ferromagnetic materials may include elements such as iron, manganese, arsenic, antimony and bismith, but are not limited to such elements. Classes of materials from which the magnetic material may be selected include CrO2, gamma-ferric oxide (both cobalt treated and non-treated) and metallic iron, cobalt or nickel. Also ferrites of general form MO.Fe2O3 where M is a bivalent metal, e.g. Mg, Mn, Fe, Co, Ni, Cu, Zn, Cd or Li, cobalt treated ferrites or magnetoplumbite type oxides (M type) with general form MO.6Fe2O3 where M is a large divalent ion such as Ba, Sr or Pb are all potentially useful magnetic materials in this application. Further, superparamagnetic, single domain particles may be used as the magnetic material. Most preferably, the ferromagnetic material is selected from the class of ferromagnetic materials known as gamma-ferric oxide, (xcex3Fe2O3).
Examples of suitable ferromagnetic materials from which the magnetic materials might be selected include Co treated gamma-ferric oxide, some non cobalt treated gamma-ferric oxides, cobalt treated ferrites and chromium dioxide.
The method of the invention provides a means to increase temperature in the area of diseased tissue to above 41xc2x0 C. to decrease the viability of malignant cells. A decrease in the viability of malignant cells results in either cell death or increased cell sensitivity to the effects of ionizing radiation or chemotherapeutic drugs.
The amount of hysteresis heat that is generated in a magnetic material during each cycle of an applied magnetic field is given by W. To turn hysteresis heat energy into power that is capable of heating tissue, the magnetic field must have a high frequency of alternation. During treatment, patients are placed into a machine that generates a magnetic field with strength H and frequency f. The higher the frequency the greater the rate of heating in the tissues that contain the magnetic microcapsules. However, the physiological response to high amplitude, high frequency magnetic fields limits the field amplitude and frequency that can be used in any clinical application. These limitations result from nerve muscle activation and eddy current heating which depends, inter alia, on the electrical conductivity of the tissue. Both of these are as a result of the electric fields induced in the tissue by the magnetic field. The size of these potentially deleterious induced electric fields is proportional to the square of the product of H, f and the radius of the exposed area, r, normal to the direction of the field. The product of H, f and r largely defines the magnetic field conditions. The product of H, f and r should not exceed a value of about 7.5xc3x97107 A/s., ie H.f.rxe2x89xa67.5xc3x97107 A/s. To illustrate this point consider the case of whole body exposure to a magnetic field applied along the body axis. In this case r is typically 0.15 m so the product of f and H should not excede about 5xc3x97108 A/m.s.
The magnetic material used in the invention may be delivered to the diseased tissue in a patient by any means known in the art. Suitable routes of administration might include: intratumoral, peritumoral and intravascular administrations (eg intra-arterial, intraperitoneal, subcutaneous or intrathecal injections). Preferably, the magnetic materials are delivered to the diseased tissue via the arterial or venous blood supply.
Preferably, the magnetic material is mixed in a liquid emulsion or is bound into microcapsules which may then be mixed with a suitable biocompatible medium for delivery into a patient. Most preferably the magnetic material is bound in a matrix material to form a microcapsule. Most magnetic particles themselves are, typically, too small and too dense to enable optimum delivery to the site of diseased tissue. Therefore, they are desirably encapsulated in microcapsules. Important properties of microcapsules are their density and their diameter. The density effects the efficiency of their carriage by the blood stream to the site of immobilisation in the diseased tissues vascular network while the size determines the proximity of the point of immobilisation to the diseased tissue.
Preferably, the magnetic material is bound in a matrix material which does not adversely effect the hysteresis or eddy current heating properties of the magnetic particles. The non-toxic binder or matrix material may comprise any of the suitable non-toxic materials which are well known in the microencapsulation art. Suitable materials include, for example, proteins, polymeric resins such as styrene-divinylbenzene, biopol, albumin, chitoxan etc.
In a preferred form of the invention, the microcapsules are adapted to bind or absorb or contain a cytotoxic material which is released upon heating of the microcapsule. For example the microcapsule may be composed of a porous, heat sensitive material which is non-toxic to and, preferably, inert to or compatible with animal tissue and which has embedded therewithin suitable magnetic material. The pores in the material are desirably filled with the cytotoxic compound. Upon hysteresis heating the micro-particles are capable of expanding, thereby permitting the release of the cytotoxic compound. Such particles should, however, be resistant to melting upon hysteresis heating. Thus, the use of such particles in the method of the present invention provides a single device with which combined chemotherapy and thermotherapy can be achieved to treat diseased tissue in a patient.
According to a further embodiment of the invention, an ionizing radiation source may be applied to the locus of the diseased tissue in conjunction with a magnetic field, said tissue having microcapsules as herein described included therein. The radiation source may be microcapsules which contain a radioactive compound such as Yttrium-90 or delivered from an external radiation source.